ESPE Abstracts

Background: We previously reported the first human mutation in mini-chromosome maintenance homologue 4 (MCM4) in a cohort of patients with adrenal failure, immunodeficiency and chromosomal fragility.

Objective and Hypotheses: To report the full endocrine phenotype of 14 patients with MCM4 mutations.

Method: Patients case notes were examined and investigations performed to fully assess adrenal function, pubertal development, gonadal function, and growth.

Results: 13 of 14 patients have developed isolated glucocorticoid deficiency with age of diagnosis ranging from 0.5 to 12 years. Five patients initially had normal adrenal function but subsequently developed glucocorticoid deficiency. All patients have undetectable DHEAS levels and low androstenedione levels. Clinically all children >8 years have absent adrenarche. Renin and aldosterone levels were normal. Children had low birth weight (average, −2.3 SDS) and subsequent short stature (−2.6 SDS). Boys showed lack of a pubertal growth spurt and final height was significantly shorter than girls (males, −2.8 SDS and females, −1.8 SDS, P=0.01). The GH and IGF1 axis was normal. Four girls were of pubertal age; all entered and progressed through puberty normally and have normal menstrual cycles. In contrast all five boys of pubertal age had severe delay of growth and puberty and one required testosterone injections to induce puberty. Initially LHRH stimulation tests showed a pre-pubertal response. Subsequently two boys showed evidence of endogenous testosterone production with normal gonadotrophins and morning testosterone levels.

Conclusion: Patients with MCM4 mutations have isolated glucocorticoid deficiency with no evidence of mineralocorticoid deficiency. Both clinically and biochemically children have no evidence of adrenal androgen production suggesting failure of development of the zona reticularis. In addition boys have evidence of a significant delay in pubertal development. This potentially indicates a role for adrenal androgen priming in male puberty or a novel function of MCM4 in pubertal development.